Crystalline antifungal polymorph

ABSTRACT

The crystalline polymorph Form I of (−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one represented by the formula I 
                 
 
pharmaceutical compositions containing such a polymorph and methods of using such a polymorph to treat fungal infections in mammals are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 09/166,445, filed, Oct. 5, 1998, now U.S. Pat. No.6,713,481, which claims the benefit under 35 U.S.C. §119(e) of U.S.provisional application Ser. No. 60/061,231, filed Oct. 7, 1997.

BACKGROUND OF THE INVENTION

This invention relates to the most stable crystalline polymorph Form Iof(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-onerepresented by the formula I (hereinafter “the compound of formula I”)

pharmaceutical compositions containing such polymorph and methods ofusing such polymorph to treat fungal infections in mammals.

International Publication Numbers WO/95/17407(published 29 Jun. 1995 andWO 96/38443(published 5 Dec. 1996) disclose methods of making thecompound of formula I and using it to treat antifungal infections inmammals. These International Patent Publications do not disclose orrefer to, or even suggest the possible existence of a crystallinepolymorph of the compound of formula I; the synthetic proceduresdisclosed therein produce the compound of formula I as an amorphoussolid.

To prepare pharmaceutical compositions containing the compound offormula I for administration to mammals in accordance with exactinghealth registration requirements of the U.S. and international healthregistration authorities, e.g. the FDA's Good ManufacturingPractices(“GMP”)requirements, there is a need to produce the compound offormula I in as pure a form as possible, especially a form havingconstant physical properties.

SUMMARY OF THE INVENTION

We have discovered that the compound of formula I can exist in the formof three crystalline polymorphs, each having distinctly different fromeach other and from the amorphous form in their physico-chemical data,their physical properties and their methods of preparation. These threenovel crystalline polymorph forms described in this specification arehereinafter referreds to as form I, form II and Form III. Of the threeforms. Form I is the most stable.

Accordingly, this invention provides a crystalline polymorph Form I of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-onerepresented by formula I

and characterized by the following x-ray powder diffraction patternexpressed in terms of “d” spacing and relative intensities(“RI”):

d spacing (±0.04) RI 6.10 Medium 4.63 Medium 4.10 Wide 3.69 Wide 3.05Wide

This invention also provides a crystalline polymorph Form Iof(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-onecharacterized by the following x-ray powder diffraction pattern(Table 1) expressed in terms of “d” spacings and relative intensities(“RI”)(S=strong, M=medium, W=weak, V=very, D=diffuse and VWD, forexample=very weak diffuse):

TABLE 1 relative d spacing intensity 22.14 VWD 12.27 VWD 11.37 M 10.35VWD 8.85 M 7.90 VWD 7.52 W 6.77 W 6.10 M 5.82 M 5.63 M 5.52 M 5.41 M5.17 W 4.95 VS 4.84 M 4.63 M 4.54 M 4.42 S 4.29 VWD 4.23 WD 4.10 W 4.02WD 3.98 M 3.86 W 3.82 W 3.76 W 3.69 W 3.63 W 3.47 M 3.45 WD 3.36 W 3.30VW 3.24 VWD 3.21 WD 3.17 VWD 3.14 VWD 3.05 W 2.99 VWD 2.95 VWD 2.90 VWD2.87 VWD 2.84 VWD 2.77 VWD 2.72 WD 2.67 VWD 2.65 VWD 2.61 VWD 2.58 VWD2.52 VWD 2.48 VWD 2.44 VWD 2.41 VWD 2.35 VWD 2.34 VWD 2.28 VWD 2.26 VWD

This invention further provides pharmaceutical composition containingthe crystalline polymorph of Forms I, and methods of treating and/orpreventing fungal infections using such a crystalline polymorph.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 presents a characteristic x-ray powder diffraction pattern of thecyrstalline polymorph of form I [Vertical Axis: Intensity (CPS, counts(square root)); Horizontal Axis: Two Theta(degrees)].

FIG. 2 presents a characteristic x-ray powder diffraction pattern of thepolymorph of form II [Vertical Axis: Intensity (CPS, counts (squareroot)); Horizontal Axis: Two Theta(degrees)]; x-ray diffractionindicates form II is partially amorphous.

FIG. 3 presents a characteristic x-ray powder diffraction pattern of thecyrstalline polymorph of form III [Vertical Axis: Intensity, (CPS,counts (square root)); Horizontal Axis: Two Theta(degrees)]

FIG. 4 presents a characteristic infrared spectrum of the crystallinepolymorph of form I in a potassium bromide pellet[Vertical Axis;Transmittance(Percent); Horizontal Axis: wavenumber (cm^(−1)].)

FIG. 5 presents a characteristic infrared spectrum of the crystallinepolymorph of form II in a potassium bromide pellet[Vertical Axis;Transmittance(Percent); Horizontal Axis: wavenumber (cm^(−1)].)

FIG. 6 presents a characteristic infrared spectrum of the crystallinepolymorph of form III in a potassium bromide pellet[Vertical Axis;Transmittance(Percent); Horizontal Axis: wavenumber (cm^(−1)].)

FIG. 7 presents a characteristic differential scanning calorimetrythermogram of the crystalline polymorph of form I [taken on a DuPont2100: Thermal Analysis under a nitrogen atmosphere; 10° C./min scanrate; single endotherm, onset temperature: about 166° C.; Vertical Axis;Heat Flow in cal/sec/g; about 166° Horizontal Axis: Temperature indegrees centigrade].

FIG. 8 presents a characteristic differential scanning calorimetrythermogram of the crystalline polymorph of form II [taken on a DuPont2100: Thermal Analysis under a nitrogen atmosphere; 10° C./min scanrate; endotherm, onset temperature about 26° C.; endotherm, onsettemperature about 90° C.; exotherm, start temperature about 113° C.;endotherm onset temperature about 163° C.; Vertical Axis; Heat Flow incal/sec/g; Horizontal Axis: Temperature in degrees centigrade]

FIG. 9 presents a characteristic differential scanning calorimetrythermogram of the crystalline polymorph of form III [taken on a DuPont2100: Thermal Analysis under a nitrogen atmosphere; 10° C./min scanrate; endotherm, onset temperature about 98° C.; exotherm, starttemperature about 114° C.; endotherm, onset temperature about 168° C.;Vertical Axis; Heat Flow in cal/sec/g; Horizontal Axis: Temperature indegrees centigrade]

FIG. 10 presents a characteristic ¹H nmr spectrum of the crystallinepolymorph of formsI, II and III[taken on a Vvarian XL400 in CDCl₃ at 400MHz with TMS as an internal standard].

DETAILED DESCRIPTION OF THE INVENTION

The crystalline polymorph Form Iof(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-oneprovides an antifungal drug having the following advantages compared toits amorphous form in the priorr art: lower impurity content and moreconsistent product quality i.e., more consistent physicalcharacteristics including more consistent color, rate of dissolution andease of handling; as well as a longer term stability.

The three crystalline polymorphic forms of the compound of formuladesignated as Form 1, II and III can readily be distinguished from oneanother by examination of the characteristic x-ray Diffraction patterns(see FIGS. 1-3), the characteristic infrared spectra (see FIGS. 4-6) andthe characteristic Differential Scanning Calorimetry (DSL) thermograms(FIGS. 7-9). Form 1, the most stable form, did not convert into anyother form under normal storage conditions (15°-30° C. and protectedfrom light) or under the following stress conditions:

-   -   150° C. for 2 hours    -   75° C. for 6 weeks    -   97% relative humidity at ambient temperature for 2 minutes    -   75% relative humidity at 40° C. for 6 weeks

The DSC thermograms shown in FIGS. 8 and 9 indicate that Form II andForm III thermally convert into the more stable Form I at temperaturesbetween 100 and 125° C. The characteristic physico-chemical data ofcrystalline polymorph Form I of the compound of Formula I are summarizedin the following Table.

TABLE Characteristic Physico-Chemical Data of Crystalline Polymorph FormI of the Compound of Formula I Melting Point Range: 164-165° C.¹Physical Appearance: white to off-white powder Specific Rotation: [a]²⁵D= −29.4°² X-ray Powder Diffraction See FIG. 1 and Table 1 Pattern:Differential Scanning FIG. 7 Calorimetry Thermogram Proton NMR SpectrumFIG. 10 ¹USP Class Ia procedure used to determine melting point range.²Concentration: 10 mg/mL in methanol.

All of these advantages inherent in the crystalline polymorph Form I ofthe compound of this invention would be useful in the development andapproval of a pharmaceutical product containing the antifungal drug offormula I.

The crystalline polymorphic form of the compound of Form I may be formedby crystallizing the compound of formula I (as the free base) using asolvent system such as acetonitrile, methanol in combination with waterin a v/v ratio of 1.5:1 to 1:1.5, preferably about 1:1; and isopropylalcohol in combination with water in a volume/volume (v/v) ratio of1.5:1 to 1:1.5, preferably about 1:1. The solvent or solvent system weretypically healed to reflux and slowly cooled to 60-40° C. with agitationand thereafter cooled slowly to room temperature (20°-25° C.) or even 0°(with acetonitrile) with continued agitation for ½ to 1 hour. Thecrystalline polymorphic form of the compound of form II may be formed bycrystallizing the compound of formula I (as the free base) using asolvent system such as acetone-water in a volume/volume (v/v) ratio of1.5:1 to 1:1.5, preferably about 1:1., or methylene chloride. The FormIII product obtained from methylene chloride also contained someamorphous form. The solvent or solvent system were typically healed toreflux and slowly cooled without agitation to room temperature (20°-25°C.) The crystalline polymorphic form of the compound of form III may beformed by adding the compound of formula I (as the free base) to asolvent system such as boiling methanol and allowing the resultingsolution to cool without agitation to room temperature.

The infrared spectrum of the crystalline polymorph of form I taken inthe form of a potassium bromide pellet is characterized by the followingpeaks:

frequency (cm⁻¹) 3118 cm−1 3055 2967 2935 2876 2830 1700 1687 1616 15511511 1451 1394 1272 1234 1136 1017 964 943 824 737 681 664

The complete infrared spectrum of the crystalline polymorph of form IItaken in the form of a potassium bromide pellet is characterized by thefollowing peaks:

frequency (cm⁻¹) 3121 cm−1 3066 2969 2934 2874 2827 1691 1616 1598 15541512 1501 1452 1420 1394 1328 1297 1272 1230 1186 1137 1101 1075 10561039 1027 965 943 915 849 824 786 738 680 660 584 545 537

The complete infrared spectrum of the crystalline polymorph of form IIItaken in the form of a potassium bromide pellet is characterized by thefollowing peaks:

frequency (cm⁻¹) 3120 cm−1 3072 3054 2971 2939 2874 2832 1699 1616 15981557 1512 1396 1271 1231 1136 1101 1075 1027 953 913 824 787 737 682 659

The infrared spectra were obtained on a Mattson Galaxy 6021 FTIRspectrometer. The potassium bromide pellets were prepared in accordancewith the USP procedure <197K>, U.S. Pharmacopeia, National Formulary,USP XXIII, NF XVIII.

The x-ray powder diffraction patterns were measured on a Philips ADP3720automated diffractometer system (model PW 1800). The radiation sourcewas copper (K-alpha) and the long fine focus tube connected to a PhilipsXRG 3100 x-ray generator at 45 KV and 40 mA. The take-off angle was 6degrees and a graphite monochromator as used. A scintillation detectorwas employed and data was acquired with a scan rate of 0.025 degrees persecond, a step size of 0.010 and a step time of 40 seconds per degree.

The x-ray powder diffraction pattern distinctive for polymorph form 1descarbonylethoxyloratadine expressed in terms of the followingdistinctive “d” spacing and relative intensties(“RI”) is providedhereinbelow:

d spacing (±0.04) RI 6.10 Medium 4.63 Medium 4.10 Wide 3.69 Wide 3.05Wide

A more complete x-ray powder diffraction pattern for the crystallinepolymorph of the compound of formula I expressed in “d” spacings andrelative intensities (“RI”) with V, M, W, V, and D defined as hereinabove is provided hereinbelow in Table 1:

TABLE 1 relative d spacing intensity 22.14 VWD 12.27 VWD 11.37 M 10.35VWD 8.85 M 7.90 VWD 7.52 W 6.77 W 6.10 M 5.82 M 5.63 M 5.52 M 5.41 M5.17 W 4.95 VS 4.84 M 4.63 M 4.54 M 4.42 S 4.29 VWD 4.23 WD 4.10 W 4.02WD 3.98 M 3.86 W 3.82 W 3.76 W 3.69 W 3.63 W 3.47 M 3.45 WD 3.36 W 3.30VW 3.24 VWD 3.21 WD 3.17 VWD 3.14 VWD 3.05 W 2.99 VWD 2.95 VWD 2.90 VWD2.87 VWD 2.84 VWD 2.77 VWD 2.72 WD 2.67 VWD 2.65 VWD 2.61 VWD 2.58 VWD2.52 VWD 2.48 VWD 2.44 VWD 2.41 VWD 2.35 VWD 2.34 VWD 2.28 VWD 2.26 VWD

The crystalline polymorph Form IIof(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-oneis characterized by the following x-ray powder diffraction patternexpressed in terms of “d” spacing and relative intensities (“RI”):

d spacing (±0.04) RI 20.05 Medium 13.84 Strong

The crystalline polymorph Form IIof(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-oneis characterized by the following x-ray powder diffraction patternexpressed in terms of “d” spacings and relative intensities(“RI”)(S=strong, M=medium, W=weak, V=very D=diffuse and VWD, forexample=very weak diffuse):

relative d spacing intensity 20.05 M 13.84 S 9.44 M 6.90 VWD 5.75 WD5.28 VWD 4.75 VWD 3.85 VWD 3.43 VWD

The crystalline polymorph Form IIIof(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-oneis characterized by the following x-ray powder diffraction patternexpressed in terms of “d” spacing and relative intensities (“RI”):

d spacing (±0.04) RI 28.69 Strong 14.45 Strong 10.59 Strong 7.27 Wide6.59 Wide 4.14 Medium 3.58 Very Strong 3.53 Medium

The crystalline polymorph form IIIof(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-oneis characterized by the following x-ray powder diffraction patternexpressed in terms of “d” spacings and relative intensities(“RI”)(S=strong, M=medium, W=weak, V=very D=diffuse and VWD, forexample=very weak diffuse):

relative d spacing intensity 28.69 S 22.51 VWD 14.45 S 11.44 VW 10.59 S9.65 W 9.41 W 8.88 W 7.90 M 7.54 VW 7.27 W 6.82 VWD 6.59 W 6.13 VWD 5.82W 5.64 W 5.57 W 5.39 M 5.29 S 5.17 VWD 5.05 W 4.94 W 4.84 W 4.72 M 4.52W 4.45 VW 4.38 VWD 4.34 V 4.28 VW 4.14 M 4.03 W 3.97 W 3.87 VW 3.77 VWD3.66 WD 3.58 VS 3.53 M 3.47 WD 3.44 WD 3.39 WD 3.36 WD 3.29 W 3.25 W3.15 VWD 3.12 VWD 3.10 WD 2.99 VWD 2.94 VWD 2.85 WD 2.81 WD 2.78 WD 2.76WD 2.72 VWD 2.71 VWD 2.69 VWD 2.64 VWD 2.58 VWD 2.53 WD 2.50 VWD 2.42VWD 2.40 VWD 2.36 WD 2.35 WD 2.32 VWD 2.26 VWD

Pharmaceutical Compositions

Pharmaceutical compositions of this invention may contain in addition toan anti-fungally effective amount of crystalline polymorph of thecompound of formula I as the active ingredient, inert pharma-ceuticallyacceptable carriers that may be solids or liquids. Solid formcompositions include powders, tablets, dispersible granules, capsules,cachets, and suppositories. A solid carrier can be one or moresubstances which may also act as diluants, flavoring agents,solubilizers, lubricants, suspending agents, binders or tabletdisintegration agents; it can also be an encapsulating material. Inpowders, the carrier is a finely divided solid which is in admixturewith the finely divided active compound. In the tablet the activecompound is mixed with carrier having the necessary binding propertiesin suitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain from about 5 to about 20 percentof the active ingredient. Suitable solid carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methycelulose, sodiumcarboxymethyl-cellulose, a low melting wax. cocoa butter and the like.The term “compositions” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, caches are included. Tablets, powders, cachets and capsulescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor topical administration. Liquid preparations can also be formulatedin solution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by adding the active component inwater and adding suitable colorants, flavors, stabilizing, sweetening,solubilizing and thickening agents as desired. Aqueous suspensionssuitable for oral use can e made by dispersing the finely divided activecomponent in water with viscous material, i.e., natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose and otherwell-known suspending agents.

Topical formulation useful for nasal or ophthalmic administration arealso contemplated. Topical formulation suitable for nasal administrationmay be solutions or suspensions. Ophthalmic formulations may besolutions, suspension or ointments. Ointments usually contain lipophiliccarriers such as mineral oil and/or petrolatum. Solution for ophthalmicadministration may contain sodium chloride, acid and/or base to adjustthe pH as well as purified water and preservatives, which normallycontains a non-toxic, pharmaceutically acceptable topical carrier may beapplied daily to the affected skin until the condition has improved.

The anti-fungally effective amount of the crystalline polymorph of thecompound of formula I for topical administration varies from 0.1 to 20%by weight of the total pharmaceutical composition, which normallycontains one or more non-toxic, pharmaceutically acceptable topicalcarriers; the pharmaceutical composition may be applied daily to theaffected area of the skin until the fungal infection has been irradiatedThe preferred amount varies from 0.5 to 10% by weight of the totalpharmaceutical composition.

The anti-fungally effective amount of the crystalline polymorph of thecompound of formula I for oral administration varies from about 1 to 30mg/day, more preferably about 1 to 20 mg/day and most preferably about 1to 10 mg/day in single or divided doses.

Parenteral forms to be injected intravenously, intramuscularly, orsubcutaneously are usually in the form of a sterile soluon, and maycontain salts or glucose to make the solution isotonic.

In general, the parenteral dosage for humans for antifungal use rangesfrom abou.25 mg per kilogram of body weight per day to about 20 mgkilogram of body weight per day being preferred.

The exact amount, frequency and period of administration of the compoundof the present invention for antifungal use will vary, of course,depending upon the sex, age and medical condition of the patent as wellas the severity of the antifungal infection as determined by theattending clinician.

General Experimental

The compounds of this invention are prepared in accordance with thefollowing Examples using commercially available starting materials.

In solution, no crystalline form exists, and thus the physiochemicalsolution characteristics, i.e. 'H nmr spectra, ultraviolet spectra andspecific rotations of the crystalline polymorph and amorphous forms ofthe compound of formula I are the same. The 'H nmr shown in FIG. 10 isconsistent with the structure of the compound of formula I. The specificrotation as measured at the D line of sodium at 25° C. is −29.4.

EXAMPLE 1A

Preparation of Crystalline Polymorph Form I of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]-methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one

One hundred and sixty four grams of the crude product produced inaccordance with Example 32 of International Patent Publication No. WO95/17407 published 29 Jun. 1995 was dissolved in refluxing methanol(1.64L). The hot solution was filtered through a pad of celite, andwarmed back to reflux. To the solution was added water (984 ml) whilemaintaining a reflux temperature. The solution was allowed to coolslowly to about 45° C. The resulting mixture was agitated for 1 hour atthis temperature, then cooled slowly to room temperature and furtheragitated for 1 hour. The solids that formed were collected by filtrationand washed with chilled methanol-water (1:1, about 524 ml). The productwas then dried in an oven (45° C., 29 psi vacuum, 24 hours) to yield156.5 g of white crystals.

EXAMPLE 1B

Preparation of Crystalline Polymorph Form I of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]-methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one

-   -   Add 95 Kg of the crude product produced in accordance with        Example 32 of International Patent Publication No. WO 95/17407        published 29 Jun. 1995 and 885 L (9×) of methanol to a first        reaction vessel blanketed with nitrogen.    -   Heat the mixture with agitation to reflux (a temperature of        60-65° C.)    -   Maintain stirred mixture at reflux for 30 minutes or until        solution is achieved    -   Pump the hot solution through an in-line tither (normally 0.22        micron) to a second reaction vessel.    -   Add 95 L (1×) methanol to first vessel.    -   Heat, with agitation, the methanol in the first reaction vessel        to reflux and pump hot methanol solution through the in-line        filter into the second reaction vessel.    -   Heat so formed solution in the second reaction vessel to a        reflux temperature of 60-65° C.    -   Slowly add 570 L (6×) of purified water USP through in-line        filter into the second reaction vessel while maintaining the        solution in the second vessel at reflux (temperature should rise        to 77° C.    -   Cool slowly the so-formed solution in the second reaction vessel        over about a 30 minute period to 70° C.    -   Stir the so-formed mixture at 70° C. to effect crystallization        and to form a slurry.    -   Cool the so-form slurry slowly over a period of at least 1 hour        to about 40° to 45° C.    -   Stir the resulting slurry at a temperature of about 40° C. to        45° C. for at least 30 minutes    -   Cool the so-formed slurry slowly over a period of at least 1        hour to room temperature (15-25° C.)    -   Continue stirring the so-formed slurry at a temperature of 15°        to 25° C. for a period of about 2 hours.    -   Filter the slurry from the second reaction vessel into a        centifuge (in two batches). Centrifuge to separate the solvent        and remove solvent.    -   Add 380 L (4×) of purified water USP and 380 L (4×) methanol to        the first reaction vessel. Stir the so-formed solution and        adjust the temperature to 15-25° C.    -   Wash each of the two batches with the chilled methanol/water        solution delivered through the in-line filter from the first        reactor and centrifuge.    -   Remove the solvent mixture from the centrifuges.    -   Transfer the two batches of solid from the centrifuges and place        them on trays.    -   Dry the solid in an air draft oven at a dryer temperature of        35°to 45° C. for about 14 hours or until the loss on drying is        ≦0.2% by weight.

EXAMPLE 2

Preparation of Crystalline Polymorph Form I of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]-methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one

Two grams (2 g) of crude the starting material prepared in accordancewith Example 1 was dissolved in refluxing isopropyl alcohol (20 mL). Tothe solution was added water (20 ml) while maintaining a refluxtemperature. The solution was allowed to cool slowly to about 63° C.when crystalization occurred. The resulting mixture was agitated for 10mins at this temperature, then cooled slowly to room temperature andfurther agitated for 1 hour. The solids that formed were collected byfiltration. The product was then dried in a draft oven (45° C., 24hours) to yield a white solid.

EXAMPLE 3

Preparation of Crystalline Polymorph Form I of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]-methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one

Five grams (5 g)of the crude starting material prepared in accordancewith Example 1 was dissolved in refluxing acetonitrile (100 mL). Thesolution was allowed to cool slowly to about 50° C. when crystallizationoccurred. The resulting mixture was agitated for 30 mins at thistemperature, then cooled slowly to 0° C. and further agitated for 30mins. The solids that formed were collected by filtration and washedwith chilled acetonitrile (25 mL). The product was then dried in an oven(40° C., 29 psi vacuum, 12 hours) to yield 3.9 g of white crystals.

EXAMPLE 4

Preparation of Crystalline Polymorph Form II of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]-methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one

Approximately 1 g of crude starting material prepared as described inExample 1 was dissolved in refluxing acetone (10 mL). Water (3 mL) wasadded to this mixture while maintaining a reflux temperature. Theresulting yellow solution was allowed to cool without agitation to roomtemperature. The solids that formed were collected by filtration andwashed with acetone-water (1:1, about 5 ml). The product was then driedin an oven (45° C., 29 psi vacuum, 24 hours) to yield 0.63 g of whitecrystals.

EXAMPLE 5

Preparation of Crystalline Polymorph Form II of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]-methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one

Approximately 1 g of crude starting material prepared as described inExample 1 was dissolved in hot 5 ml methylene chloride and was allowedto dry slowly in a fume hood. A form II material was obtained togetherwith some amorphous form.

EXAMPLE 6

Preparation of Crystalline Polymorph Form III of(−)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]-methoxy]phenyl]-1-piperazinyl]phenyl-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxylpropyl]-3H-1,2,4-triazol-3-one

Approximately 2 g g of crude starting material prepared as described inExample 1 was dissolved in hot 10 ml methanol. The resulting solutionwas allowed to cool without agitation to room temperature in a fumehood. The solids that formed were collected by filtration and dried inthe fume hood.

1. A crystalline polymorph Form I of the compound represented by theformula I

and characterized by at least one of the following properties: a meltingpoint range of about 164 to about 165° C. wherein the melting pointrange is determined using USP Class Ia procedure; a specific rotationequal to [a]²⁵ _(D)=−29.4° wherein the specific rotation is determinedusing a concentration of 10 mg/ml in methanol; an X-ray powderdiffraction pattern substantially similar to that presented in FIG. 1; adifferential scanning calorimetry thermogram substantially similar tothat presented in FIG. 7; or the proton NMR spectrum substantiallysimilar to that presented in FIG.
 10. 2. A pharmaceutical compositioncomprising an anti-fungally effective amount of the crystallinepolymorph form I of claim 1 and a pharmaceutically acceptable carrier.3. A method of treating and/or preventing fungal infections in a mammalwhich comprises administering to said mammal an anti-fungally effectiveamount of the crystalline polymorph form I of claim
 1. 4. A crystallinepolymorph Form III of the compound represented by the formula I

and characterized by an X-ray powder diffraction pattern displaying dspacing peaks at 28.69, 14.45, 10.59, 7.27, 6.59, 4.14, 3.58, and 3.53+/−0.04.
 5. The crystalline polymorph Form III of claim 4 furthercharacterized by an X-ray powder diffraction pattern substantiallysimilar to that presented in FIG.
 3. 6. A pharmaceutical compositioncomprising an anti-fungally effective amount of the crystallinepolymorph Form III of claim 4 and a pharmaceutically acceptable carrier.7. A method of treating and/or preventing fungal infections in a mammalwhich comprises administering to said mammal an anti-fungally effectiveamount of the crystalline polymorph Form III of claim 4.